Fra-2/AP-1 regulates melanoma cell metastasis by downregulating Fam212b
Fra-2/AP-1 regulates melanoma cell metastasis by downregulating Fam212b
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DOI：
10.1038/s41418-020-00660-4
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发表时间：
2020-11-13
影响因子：
12.4
通讯作者：
Bozec, Aline
中科院分区：
文献类型：
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作者：
Chen, Guang-Liang;Li, Rui;Bozec, Aline
转移性黑色素瘤仍然是一种具有挑战性的疾病。因此，了解黑色素瘤如何转移的分子机制是有意义的。在此，我们表明，在黑色素瘤细胞中的AP-1转录因子成员Fra-2的下调与侵袭性黑色素瘤表型在体外和体内。在体外，Fra-2敲低黑色素瘤细胞促进细胞迁移和侵袭与增加的Snail-1，Twist-1/2，和基质金属蛋白酶-2（MMP-2）的表达。在体内，黑色素瘤细胞系中的Fra-2敲低导致向肺和肝的转移增加。Fra-2敲低黑色素瘤细胞的转移潜力增加可能是由于细胞周期转换加速和组织血管生成增加。使用Fra-2敲低细胞系微阵列分析，我们鉴定了蛋白Fam 212 B（具有序列相似性212成员B的家族）作为Fra-2的下游靶标。通过在Fra-2突变细胞中额外敲低Fam 212 b，我们减轻了由Fra-2敲低诱导的细胞迁移、侵袭和细胞周期转换表型。此外，Fam 212 b过表达增强β-连环蛋白通路。最后，Fam 212 b表达与人类患者中黑色素瘤转移增加和临床结果差相关。总之，这些发现揭示了Fra-2-Fam 212 b轴作为黑色素瘤转移的新途径，其可以在未来用作黑色素瘤转移特性的潜在标志物。
Metastatic melanoma remains a challenging disease. Understanding the molecular mechanisms how melanoma becomes metastatic is therefore of interest. Herein we show that downregulation of the AP-1 transcription factor member Fra-2 in melanoma cells is associated with an aggressive melanoma phenotype in vitro and in vivo. In vitro, Fra-2 knockdown in melanoma cells promoted cell migration and invasion associated with increased Snail-1, Twist-1/2, and matrix metalloproteinase-2 (MMP-2) expression. In vivo, Fra-2 knockdown in a melanoma cell line led to increased metastasis into the lungs and liver. The increased metastatic potential of Fra-2 knockdown melanoma cells was likely due to an accelerated cell cycle transition and increased tissue angiogenesis. Using Fra-2 knockdown cell lines microarray analysis, we identified the protein Fam212b (family with sequence similarity 212 member B) as a downstream target of Fra-2. By additional knockdown of Fam212b in Fra-2 mutant cells, we mitigated the cell migration, invasion, and cell cycle transition phenotype induced by Fra-2 knockdown. Furthermore, Fam212b overexpression enhanced beta-catenin pathway. Finally, Fam212b expression is correlated with increased melanoma metastasis and poor clinical outcomes in human patients. In summary, these findings reveal the Fra-2-Fam212b axis as a new pathway of melanoma metastasis, which can be in the future used as potential marker of the metastatic properties of melanoma.